REQUIREMENT OF THE YEAST RTH1 5' TO 3' EXONUCLEASE FOR THE STABILITY OF SIMPLE REPETITIVE DNA

Simple repetitive DNA sequences are unstable in human colorectal cance rs and a variety of other cancers. Mutations in the DNA mismatch repai r genes MSH2, MLH1, and PMS1 result in elevated rates of spontaneous m utation and cause a marked increase in the instability of simple repea ts. Compared with the wild type, a null mutation in the yeast RTH1 gen e, which encodes a 5' to 3' exonuclease, was shown to increase the rat e of instability of simple repetitive DNA by as much as 280 times and to increase the spontaneous mutation rate by 30 times. Epistasis analy ses were consistent with the hypothesis that this RTH1-encoded nucleas e has a role in the MSH2-MLH1-PMS1 mismatch repair pathway.